New cinnamoic compounds, the process for preparing same and the use thereof in therapeutics

ABSTRACT

Compounds of formula: ##STR1## wherein: Ar is an aromatic group; R and R 1  are H or CH 3  ; A represents a nitrogenized heterocyclic radical; B is OH or forms with the adjacent CO group, either an amido group, or a carbonyloxy group; R 2  and R 3  are H or alkyl; m=0 or 1; and n=0, 1, 2 or 3. 
     These compounds are useful as drugs having stimulating, protecting and/or correcting activities of the cerebral functions.

This is a continuation of application Ser. No. 654,250 filed Sept. 25,1984, now abandoned.

The present invention relates to new cinnamoic compounds, the processfor preparing same and the use thereof in therapeutics.

The compounds of the invention comprise more precisely:

the derivatives of the following general formula: ##STR2## in which:

Ar represents a phenyl nucleus; a phenyl nucleus substituted by one ormore halogen atoms, by one or more alkoxy groups with 1 to 4 carbonatoms or by one or more hydroxyl groups; a 1,3-benzodioxol ##STR3##2,2-dimethyl-1,3-benzodioxol ##STR4## or 1,4-benzodioxanyl ##STR5##group); or a group with structure ##STR6## in which p has the value 1 or2;

R and R₁ each represent a hydrogen atom or methyl group, R and R₁,however not representing a methyl group simultaneously;

CO-A-- represents one of the following assemblies: ##STR7## where q=1 or2, R₄ represents the hydrogen atom or an alkyl group with 1 to 4 carbonatoms, s has the value 0, 2 or 3 and r has the value 0 or 1;

B represents a group chosen from the following: OH; NH₂ ; alkyloxy with1 to 4 carbon atoms; benzyloxy; N-alkylamino or N,N-dialkylamino inwhich the alkyl residues have 1 to 4 carbon atoms; pyrrolidino;piperidino; morpholino; hexamethyleneimino; nortropanic ##STR8##N-lactamic; ##STR9## where t has the value 1, 2, 3 or 4, R₄ representsthe hydrogen atom or an alkyl group with 1 to 4 carbon atoms, R₅represents an alkyl group with 1 to 4 carbon atoms and R₆ represents analkyl group with 1 to 4 carbon atoms or a benzyl or allyl group;##STR10## where v has the value 2 or 3 and ##STR11## represents either aN,N-dialkylamino group in which the alkyl residues have 1 to 4 carbonatoms, or a pyrrolidino, piperidino, morpholino radical, R₄ having thesame meanings as previously;

R₂ and R₃ each represent a hydrogen atom or alkyl group with 1 to 4carbon atoms, R₂ and R₃ not however representing simultaneously an alkylgroup comprising more than one carbon atom;

m has the value 0 or 1; and

n has the value 0, 1, 2 or 3; including the enantiomers anddiastereoisomers forms and the trans (E) and cis (Z) forms;

as well as the addition salts with organic or mineral acids or basis,the N-oxides, the quaternary ammoniums (especially the iodomethylates)and the hydrates of the above-mentioned derivatives (I);

B however not being able to represent:

* the OH, NH₂, alkyloxy with 1 to 4 carbon atoms, benzyloxy,N-alkylamino or N,N-dialkylamino group, in which the alkyl residues have1 to 4 carbon atoms, or a pyrrolidino, piperidino, morpholino,hexamethyleneimino or nortropanic group, when ##STR12## and m=n=0, and

* the NH₂, N-alkylamino or N,N-dialkylamino group in which the alkylresidues have 1 to 4 carbon atoms, or a pyrrolidino, piperidino,morpholino, or hexamethyleneimino group, when Ar represents the2,3,4-trimethoxyphenyl or 3,4,5-trimethoxyphenyl group, ##STR13## andthe set (R, R₁, R₂, R₃, m, n)=(H, H, CH₃, H, 0, O) or (H, H, H, H, 1,O); and

R and R₁ being able to represent only the hydrogen atom when CO--A-- hasthe value ##STR14## these restrictions concerning B, R and R₁ nothowever applying to the N-oxides and quaternary ammoniums mentionedabove.

A/ The process according to the invention for preparing the derivatives(I) of the particular formula: ##STR15## in which:

Ar₁ has the same meanings as Ar in (I), except for the cases where Arrepresents a phenyl nucleus substituted by one or more hydroxyl groupsor the group ##STR16## with p=1 or 2,

COA₁ -- represents one of the following assemblies: ##STR17## where q,r, s and R₄ have the same meanings as in I,

B₁ has the same meanings as B in (I), except for the values: OH,##STR18## and ##STR19## where t, R₄ and R₆ have the meanings as in (I),

R, R₁, R₂, R₃, m and n have the same meanings as in (I), consists incondensing the compounds of formula: ##STR20## in which Ar₁, R, R₁ andCOA₁ -- have the same meanings as in (Ia) with the compound of formula:##STR21## in which m, n, R₂, R₃ and B₁ have the same meanings as in (Ia)and X represents a good leaving group such as Cl for example. Thiscondensation is preferably carrier out in an organic solvent as acetone,acetonitrile, methylethylketone, ethanol, ethyl acetate, D.M.F., T.H.F.or methylene chloride in the presence of an organic or mineral base,more particularly sodium or potassium carbonate.

B/ The process of the invention for preparing the derivatives (I) of theparticular formula: ##STR22## in which Ar₁, R, R₁, R₂, R₃, B₁, m and nhave the same meanings as in (Ia) and COA₂ -- represents one of thefollowing assemblies: ##STR23## where q, r, s and R₄ have the samemeanings as in (I) consists: 1--either in condensing, in accordance withthe so-called "BOISSONNAS" reaction, in the presence of an organic basic(preferably triethylamine) and an alkyl chloroformate such as ethyl orisobutyl chloroformate, in an aprotic solvent (such as chloroform,methylene chloride, DMF or THF) the acids of formula: ##STR24## in whichAr₁, R and R₁ have the same meanings as in (Ib) with the derivatives offormula: ##STR25## in which A₂, B₁, R₂, R₃, m and n have the samemeanings as in (Ib),

2--or in condensing the acids (IV) with the derivatives (V) in thepresence of N-hydroxybenzotriazole, D.C.C.I. and a base such astriethylamine in an aprotic organic solvent such as THF,

3--or in condensing the acid chlorides of the acids (IV) (chloridesobtained for example by action of thionyl chloride on the acids (IV)according to conventional methods) with the compounds (V) in an aproticmedium such as toluene or methylene chloride in the presence of a basesuch as triethylamine.

C/ The process of the invention for preparing the derivatives (I) of theparticular formula: ##STR26## in which Ar, R₂, R₃, m and n have the samemeanings as in (I) and B₁ has the same meanings as in (Ia), consists incondensing in an alcohol medium, in the presence of a base such as NaOH,the aldehydes of formula:

    Ar--CHO                                                    (VI)

in which Ar has the same meanings as in (I) with the derivatives offormula: ##STR27## in which R₂, R₃, B, m and n have the same meanings asin (Ic), this condensation being followed by an acid treatment when, in(Ic), Ar represents a substituted phenyl nucleus having at least onehydroxyl group or the group ##STR28## (with p=1, 2).

D/ The process of the invention for preparing trans derivatives (I) inwhich B represents the group OH or a chain ##STR29## or ##STR30## inwhich t, R₄ and R₆ have the same values as in (I), consists inhydrolysing the ester group of the derivatives (I) of the particularformula: ##STR31## in which Ar, R, R₁, R₂, R₃, A, m and n have the samemeanings as in (I) and --B₂ represents a group ##STR32## , ##STR33## or##STR34## where t, R₄ and R₆ have the same meanings as in (I). Thishydrolysis is preferably carried out with hydrochloric acid diluted inacetic acid or with trifluoroacetic acid in an organic solvent such asmethylene chloride.

E/ The process of the invention for preparing the trans derivatives (I)for which Ar designates a phenyl nucleus substituted by one or morehydroxyl groups or the group ##STR35## (with p=1 or 2), consists intreating, by means of ammonia in a methanol medium, the mixed carbonatesof formula: ##STR36## in which R₉ represents an alkyl group with 1 to 4carbon atoms, x has the value 1 or 2, y has the value 0, 1 or 2 (withthe restriction that x has the value 2 only when y=0), R, R₁, R₂, R₃, mand n have the same meanings as in (I), B₁ has the same meanings as in(Ia) with CO--A₃ -- has the same meanings as CO--A-- in (I), except forthe value ##STR37##

F/ The process of the invention for preparing the derivatives (I) of theparticular formula: ##STR38## in which Ar₁, R, R₁, R₂, R₃, m and n havethe same meanings as in (Ia), A has the same meanings as in (I) and B₃represents an N-alkylamino or N,N-dialkylamino group whose alkylresidues have 1 to 4 carbon atoms, a pyrrolidino, piperidino,morpholino, hexamethyleneimino or nortropanyl group or the groups##STR39## in which t, R₄, R₅ and R₆ have the same meanings as in (I),consists in condensing in accordance with the operating method describedin paragraph B/2-, the acids of formula: ##STR40## in which Ar₁, R, R₁,R₂, R₃, A, m and n have the same meanings as in (Ie) with the amines offormula:

    H--B.sub.3                                                 (XV)

in which B₃ has the same meanings as in (Ie), the compounds (If) beingobtained by the method described in paragraph D/.

G/ The process of the invention for preparing the derivatives (I) forwhich the chain ##STR41## is cis (Z), consists in a photochemicalisomerisation of the corresponding trans (E) derivatives according tothe method described in French Pat. No. 82 03045.

H/ The derivatives (I) of the present invention may be salified by theusual methods. The salification may for example be obtained by action onthese derivatives of a mineral acid such as hydrochloric acid or anorganic acid such as maleic acid, this operation being preferablycarried out in a solvent or a mixture of solvents such as acetone,ethanol or water or else by addition of an organic or mineral base underthe same conditions.

I/ The N-oxides of the invention are prepared by the usual methodspreferably by action of organic peracids (such as M.C.P.B.A. orpara-nitroperbenzoic acid) in an aprotic solvent such as methylenechloride preferably, on the derivatives (I) of the invention.

J/ The quaternary ammoniums of the derivatives (I) of the invention andespecially the iodomethylates are prepared by action of alkyl chloridepreferably methyl iodide, on the derivatives (I) in solution in anorganic solvent by the usual methods.

K/ The enantiomers of the derivatives (I) of the invention are obtainedeither by conventional resolution methods, from salts of the derivatives(I) [salts obtained by action of an optically active organic acid onderivatives (I)], or by stereospecific synthesis by the methodsdescribed in the preceding paragraphs A/, B/, C/, but with the opticallyactive compounds (III), (V) and (VII).

The disastereoisomers are obtained in the form of diastereoisomerspairs, by chromatography on a silica or alumina column.

The compounds (II) for which COA₁ -- represents the group ##STR42## inwhich q=1 or 2 are obtained by condensation of piperazine orhomopiperazine with the acid chlorides of the acids of formula (IV).

The compounds (II) for which COA₁ -- represents the group ##STR43## areobtained by basic hydrolysis of the compounds of formula: ##STR44## inwhich Ar₁, R and R₁ have the same meanings as in (II) and COA'₁ -- hasthe same meanings as COA₁ -- in (II), except for the value ##STR45##

The compounds (IIa) are themselves obtained by condensation, by one orother of the methods described in the above paragraph B/, of the acids(IV) with the derivatives of formula:

    H--A'.sub.1 --COCF.sub.3                                   (IX)

in which A'₁ -- has the same meanings as in (IIa).

The compounds (IX) are obtained by catalytic hydrogenolysis (preferablywith palladium on charcoal) of the compounds of formula:

    R.sub.10 --A'.sub.1 --COCF.sub.3                           (X)

in which R₁₀ represents a benzyl or benzyloxycarbonyl group and A'₁ hasthe same meanings as in (IIa), the compounds (X) being obtained byaction of trifluoroacetic anhydride on the compounds of formula:

    R.sub.10 --A'.sub.1 --H                                    (XI)

in which R₁₀ and A'₁ have the same meanings as in (X).

The compounds (III) of the particular formula: ##STR46## in which B'₁represents an amino, N-alkylamino or N,N-dialkylamino group whose alkylresidues have 1 to 4 carbon atoms, or a pyrrolidino, piperidino,morpholino, hexamethyleneamino, nortropanic, N-lactamic, ##STR47## groupwherein t, v, R₄, R₅, R₆ and ##STR48## have the same meanings as in (I)and X, R₂, R₃, m and n have the same meanings as in (III) are obtainedby condensation of the compounds: ##STR49## in which X, R₂, R₃, m and nhave the same meanings as in (III), with the compounds of formula:

    HB'.sub.1                                                  (XIII)

in which B' has the same meanings as in (IIIa).

These condensations are carried out in the presence of an organic base,such as triethylamine preferably, and in aprotic solvents such astoluene, methylene chloride or THF for preference.

The compounds (XIII) for which B'₁ represents the groups ##STR50## inwhich t, R₄, R₅ and R₆ have the same meanings as in (I) are obtained bythe conventional methods described in the litterature and particularlythe methods described in J. Chem. Soc. 1965, 7305.

The compounds (V) for which HA₂ -- represents the group ##STR51## or##STR52## in which q, r and s have the same meanings as in (I) areobtained by condensation preferably in 96 ethanol, of the compounds offormula (III) respectively with piperazine, homopiperazine or thehydroxylated derivatives of formula ##STR53## in which r and s have thesame meanings as in (I).

The compounds (V) of the particular formula: ##STR54## in which H--A'₂-- represents the group ##STR55## or ##STR56## in which R₄, r and s havethe same meanings as in (I) are obtained by basic hydrolysis of thecompounds of formula: ##STR57## in which A'₂, R₂, R₃, B₁, m and n havethe same meanings as in (Va).

The compounds (XIV) are obtained by condensation of the compounds offormula (III) with the compounds of formula (IX).

The compounds (VII) are obtained by condensation of the compound offormula: ##STR58## on the compounds (III), this condensation beingcarried out by the method of process A/ above.

Finally, the compounds (VIII) are obtained by the so-called "BOISSONNAS"reaction using the method described in paragraph B/1- between the acidsof formula: ##STR59## in which R and R₁, x and y have the same meaningsas in (VIII), either with the compounds (V) or with the compounds (IX),but doubling the amounts of alkyl chloroformate and triethylamine used.In the case of condensation of compounds (IVa) with compounds (IX), thereaction is then followed by a basic treatment (K₂ CO₃ in methanol) andcondensation, by the method described in paragraph A/ above, of thecompounds (III) on the compounds obtained by formula: ##STR60## in whichR₉, x, y, R and R₁ have the same meanings as in (VIII) and A'₁, has thesame meanings as in (IIa).

The following preparations are given by way of non limitative examplesto illustrate the invention.

EXAMPLE 1 E-1-(3,4-dioxymethylene cinnamoyl) 4-(2-pyrrolidino carbonylethyl) piperazine hydrochloride [(I), code number 2]

A suspension of 10.8 g of E-3,4-dioxymethylene cinnamoyl piperazine(II), 8.7 g of 1-chloro-2-pyrrolidinocarbonyl ethyl (III) and 5.8 g ofpotassium carbonate in 50 ml of ethanol is heated to reflux for 10hours. Then it is filtered, the filtrate is evaporated, the residue istaken up in methyl ethyl ketone, washed with water, dried on sodium (ormagnesium) sulfate, filtered, the filtrate is evaporated and the residuecrystallized in isopropylic ether. The product obtained is dissolved inethanol; hydrochloric ethanol is added and the precipipate obtained isfiltered. Thus 8.5 g of the expected product are obtained, of which thephysical and analytical data are given in table I below.

By the same process, but from the corresponding reagents compounds areobtained shown in table I under code numbers 3, 4, 6, to 10, 17, 19, 20,24, 29 to 31, 33, 35, 38, 40, 44 to 47, 49 to 54, 57 to 59, 63, 64, 68and 69, as well as the compounds (V) for which H--A₂ -- represents thegroup ##STR61## or ##STR62## and the compounds (XIV), (VII) and (VIII)(from the compounds IIb).

EXAMPLE 2 tertiobutyl E-N-4-[2-[1-(4-methoxy-3-isobutyloxycarbonyloxycinnamoyl) 4-piperazino]acetamido]butanoate (VIII)

To a solution of 5 g of E-3-hydroxy 4-methoxy cinnamic acid (IVa) in 50ml of THF are added 5.3 g of triethylamine, then the solution is cooledto -10° C. and 7 g of isobutyl chloroformate are added in 20 minutes. Itis left under agitation for 15 minutes then a solution of 7.4 g oftertiobutyl N-4-[2-(N-piperazino)acetamido]butanoate (V) are introducedin 40 minutes. They are left in contact for 15 minutes, then filtered,the filtrate is evaporated, the residue is taken up in ethyl acetate,washed in water, then with a dilute aqueous solution of sodiumcarbonate, then with water, dried on sodium or magnesium sulfate,filtered, the filtrate is evaporated and the residue crystallized inisopropylic ether. 10.9 g of the expected product are obtained (Yield:75%).

Melting point: 80° C.

Empirical formula: C₂₉ H₄₃ N₃ O₈

Molecular weight: 561.66

By the same process, but from the corresponding reagents, the compoundsshown in table I under the code numbers 2 to 4, 6, 8 to 10, 17, 19, 20,22, 23, 29 to 31, 33, 35, 38, 40, 49 to 54, 58, 59, 61, 65 and 66 areobtained, as well as the compounds of formula (IIa).

EXAMPLE 3 E-1-(3,4-dioxymethylene cinnamoyl 4-[(4-pyrrolidinocarbonyl)butyl]piperazine maleate [(I), code number 17]

A mixture of 4.5 g of E-5-[4-(3,4-methylenedioxy cinnamoyl)1-piperizinyl]pentanoic acid [(If); code number 15], 0.9 ml ofpyrrolidine, 1.8 g of 1-hydroxy benzotriazole, 1.5 ml of triethylamineand 2.3 g of D.C.C.I. in 100 ml of THF is left under agitation for 12hours at 20° C. Then the insoluble portion is filtered, the filtrateevaporated and the residue is chromatographed on a silica column,(M.P.L.C.); by elution using the methylene chloride 98%-methanol 2%mixture, 3.8 g of the expected product was obtained in base form (Yield:85%) which is dissolved in acetone. An acetone solution of maleic acidis added, then the mixture is cooled and the precipitate obtained isfiltered which corresponds to the expected salt.

By the same process, but from the corresponding reagents, the compoundsshown in table I under code numbers 2 to 4, 8 to 10, 18 to 20, 22, 23,26 27, 29 to 31, 33, 35, 38, 40, 44, 45, 49 to 54, 56 to 59, 61, 65 and66 are obtained as well as the compounds of formula (IIa).

EXAMPLE 4A E-2-[4-(3,4-methylenedioxy cinnamoyl)1-piperazinyl]2-pyrrolidino carbonyl ethyl, S(+) enantiomer [(I), codenumber 4]

To a solution of 2.5 g of E-2-piperazino 2-pyrrolidino carbonyl ethylS(-) [(V)] in 50 ml of methylene chloride is added 1.2 g oftriethylamine, then 2.5 g of the acid chloride of 3,4-methylenedioxycinnamic acid (IV). It is left under agitation for 3 hours at 20° C.,then washed with water, the organic phase is decanted and evaporated,the residue is taken up in 50 ml of 1N hydrochloric acid, filtered, thefiltrate is washed with ethyl acetate, neutralized by means of NH₄ OH,extracted with methylene chloride, dried on sodium or magnesium sulfate,filtered ans the filtrate is evaporated and the residue chromatographedon a silica column (M.P.L.C.). By elution using the methylene chloride95%-methanol 5% mixture, 2.4 g of the expected product are obtained(Yield: 53%).

By the same process, but from the corresponding reagents, the compoundsshown in table I under code numbers 2, 3, 6, 8 to 10, 17, 19, 20, 22,23, 29 to 31, 33, 35, 38, 40, 49 to 54, 58, 59, 61, 65 and 66 areobtained, as well as the compounds of formula (IIa) and (IIIa).

EXAMPLE 4B E-N-(3,4-dioxymethylene cinnamoyl) piperazine (II)

A mixture of 250 g of E-3,4-dioxymethylene cinnamic acid (IV) in 875 mlof thionyl chloride are heated to reflux for 40 minutes. Then theunreacted thionyl chloride is distilled, the residue is taken up intoluene, the toluene is evaporated, the residue is crystallized inpetroleum ether and filtered (273 g). The product obtained is slowlyadded to 20° C. to a solution of 224 g of anhydrous piperazine in 1800ml of acetic acid (solution previously obtained by slowly adding thepiperazine to acetic acid at 40° C.). Then it is left under agitationfor 12 hours, filtered, the filtrate is basified with NaOH pellets, theformed precipitate is extracted with methyl ethyl ketone, the obtainedsolution is evaporated and the residue crystallized in toluene. 110 g ofthe expected product are obtained.

Melting point: 135° C.

Yield: 32%

Empirical formula: C₁₄ H₆ N₂ O₃

Molecular weight: 260.28

Elementary analysis:

    ______________________________________                                                  C          H      N                                                 ______________________________________                                        Calculated (%)                                                                            64.60        6.20   10.76                                         Obtained (%)                                                                              64.29        6.27   10.50                                         ______________________________________                                    

EXAMPLE 5 E-4-(3,4-dioxymethylene cinnamoyl) 1-pyrrolidinocarbonylmethylpiperidine, hydrated hydrochloride [(I), code number 18]

A mixture of 5.4 g of piperonal (VI), 6.8 g of 4-acetyl1-pyrrolidinocarbonylmethyl piperidine (VII) and 7.1 ml of concentratedNaOH in 80 ml of ethanol is left under agitation for 3 days at roomtemperature, then the solvents are evaporated, the residue is taken upin ethyl acetate, washed with water, dried on sodium or magnesiumsulfate, filtered, the filtrate is evaporated and the residuechromatographed on a silica column (M.P.L.C.). By elution using themethylene chloride 96%--methanol 4% mixture, 5.5 g of an oily productwere obtained which was dissolved in acetone, ≈6N hydrochloric ethanolis added, the mixture is cooled, the precipitate formed is filtered andrecrystallized in absolute ethanol; thus 3.5 g (Yield: 30%) of theexpected product were obtained.

By the same process, but from the corresponding reagents, the compoundsshown in Table I under code number 26 and 27 were obtained.

EXAMPLE 6 E-N-4-[1-[4-(3,4-dioxymethylenecinnamoyl)piperazinyl]methylcarbonylamino]butyric acid [(I), code number1]

To 50 ml of trifluoroacetic acid cooled to 5° C. is added, whilestirring, a solution of 9.2 g of the tertiobutylic ester ofE-4-[1-[4-(3,4-dioxymethylene cinnamoyl)piperazinyl]methylcarbonylamino]butyric acid (Id), prepared as describedin the above examples 1, 2, 3 or 4A, in 20 ml of methylene chloride,without the temperature of the reaction medium exceeding 20° C.(addition in about 15 minutes). Then it is left under agitation for 12hours, the solvents are evaporated, the residue is taken up in water,the aqueous phase is washed with ethyl ether, the pH is brought to ˜5with NH₄ OH, the mixture is extracted with ethyl acetate, the extract isdried on magnesium sulfate, filtered and the filtrate evaporated. Theresidue is crystallized in ethyl acetate, then recrystallized inmethanol. 2.9 g of the expected product are thus obtained.

By the same process, but from the corresponding reagents, the compoundsshown in Table I under the code numbers 11 to 16, 28, 32, 34, 36, 37,39, 41 to 43, 48 and 67 are obtained.

EXAMPLE 7 tertiobutyl E-N-4-[2-[1-(4-methoxy3-hydroxycinnamoyl)4-piperazino]acetamido]butanoate. (I)

A solution of 10.8 g of tertiobutyl E-N-4-[2-[1-(4-methoxy 3isobutyloxycarbonyloxy cinnamoyl) 4-piperazino]acetamido]butanoate[(VIII), prepared according to example 2] in 150 ml of ammonia gazsaturated methanol for 2 days at 20° C. Then the solvents are evaporatedand the residue is chromatographed on a silica column (H.P.L.C.). Byeluting with the methylene chloride 95%--methanol 5% mixture and thenwith the methylene chloride 92.5%--methanol 7.5% mixture, 8.1 g of theexpected product are obtained (Yield: 91%).

Empirical formula: C₂₄ H₃₅ N₃ O₆

Molecular weight: 461.54

By the same process, but from the corresponding reagents, the compoundsshown in Table I under code numbers 21 and 25 are obtained.

EXAMPLE 8 E-4-amino 1-(3,4-dioxymethylene cinnamoyl)piperidine (II)

A mixture of 10.2 g of E-4-trifluoromethylcarbonylamino1-(3,4-dioxymethylene cinnamoyl)piperidine (IIa) and 24.5 g of K₂ CO₃ in250 ml of methanol and 100 ml of water is left under agitation for 12hours at ambient temperature. Then the solvents are evaporated, theresidue is taken up in chloroform, the mixture is washed with water,dried on sodium or magnesium sulfate, filtered and the filtrate isevaporated. Thus the expected crystallized product is obtained.

Melting point: 120° C.

Yield: ˜100%

Empirical formula: C₁₅ H₁₈ N₂ O₃

Molecular weight: 274.31

By the same process, but from the corresponding reagents, the othercompounds of formula (II) are obtained from the corresponding compounds(IIa), as well as the compounds of formula (V) from the compounds (XIV)and the compounds of formula (IIb) resulting from the condensation ofthe compounds (IVa) and (IX).

EXAMPLE 9 1-benzyl 4-trifluoromethylcarbonylamino piperidine (X)

To a solution cooled to 0° C. of 86 g of 1-benzyl 4-amino piperidine(XI) in 350 ml of pyridine are slowly added (in two hours) 75 ml oftrifluoroacetic anhydride. Then it is left for 30 minutes between 0° and10° C., the solution is poured into 1500 ml of iced water, extractedwith ether, the extract is washed with water, dried on sodium ormagnesium sulfate, filtered, the filtrate is evaporated, the residue istaken up in isopropylic ether, the insoluble portion is filtered and thefiltrate is evaporated. Thus the expected crystallized product isobtained.

Melting point: 125° C. Yield: 72%

Empirical formula: C₁₄ H₁₇ F₃ N₂ O

Moleuclar weight: 286.29

By the same process, but from the corresponding reagents, the othercompounds (X) are obtained.

EXAMPLE 10 4-trifluoromethylcarbonylamino piperidine (IX)

A suspension of 92 g of 1-benzyl 4-trifluoromethylcarbonylaminopiperidine (X) and 9 g of wet 10% palladium on charcoal in 1000 ml ofmethanol is left under agitation for 8 days in a hydrogen atmosphere atroom temperature. Then it is filtered, the filtrate is evaporated andthe residue chromatographed on a silica column (M.P.L.C.). By elutingwith pure methanol, 44 g of the expected product are obtained.

Melting point: 111° C.

Yield: 70%

Empirical formula: C₇ H₁₁ F₃ N₂ O

Molecular weight: 196.17

By the same process, but from the corresponding reagents, the othercompounds (IX) are obtained.

EXAMPLE 11 iodomethylate of E-4-(3,4-methylenedioxycinnamoyloxy)1-pyrrolidinocarbonylmethyl piperidine [(I), code number 62]

To a solution of 4.3 g of E-4-(3,4-methylenedioxycinnamoyloxy)1-pyrrolidinocarbonylmethyl piperidine [(I), code number 61] in 50 ml ofmethylene chloride are added, at room temperature, 2.5 ml of methyliodide, then it is left under agitation for 12 hours, sheltered from theair. Then it is filtered, the precipitate is washed on the filter withmethylene chloride, then it is dried in a good vacuum. 5 g (Yield: 85%)of the expected product are obtained.

By the same process, but from the corresponding reagents, the compoundshown under code number 55 in table I was obtained.

EXAMPLE 12 E-4-(3,4-methylenedioxycinnamoyl) 1-pyrrolidinocarbonylmethylpiperazine, N-oxide [(I), code number 60]

To a solution of 7.4 g of E-4-(3,4-methylenedioxycinnamoyl)1-pyrrolidinocarbonylmethyl piperazine in 400 ml of chloroform areadded, in small portions over 20 minutes at room temperature, 4.9 g ofparanitroperbenzoic acid. Then it is left under agitation for 30 minutesand filtered, the filtrate is washed with a sodium bicarbonate solution,then with water, dried on sodium or magnesium sulfate, filtered and thefiltrate evaporated. The residue is taken up in water and the aqueousphase is then continuously extracted using methylene chloride. Theorganic phase is then dried on sodium sulfate. Then it is fitlered, thefiltrate is evaporated and the residue crystallized in ethyl ether. 5 g(Yield: 64.5%) of the expected product are obtained.

EXAMPLE 13 E-R-(-)-1-[1-[4-(3,4-dioxymethylene cinnamoyl)piperazinyl]1-pyrrolidinocarbonyl ethyl [(I), code number 5]

A suspension of 7 g of (+) binaphthyl phosphoric acid in 50 ml ofmethanol is heated to 50° C. Then a solution of 7.7 g ofE-1-[1-[4-(3,4-dioxymethylene cinnamoyl)piperazinyl]]1-pyrrolidinocarbonyl ethyl [(I), code number 3] in 20 ml of ethanol isintroduced therein. It is left under agitation for 4 hours, thenfiltered, the precipitate is rinced with ethanol and dried at 80° C. ina good vacuum. 6.34 g of salt are obtained which is taken up in water,basified with NH₂ OH, the solution obtained is extracted with ethylacetate, the organic phase is evaporated and the residue chromatographedon a silica column. Eluted with the ethyl chloride 95%--methanol 5%,then methylene chloride 90%--methanol 10% mixtures, 1.76 g (Yield: 26%)of the expected product are obtained.

    TABLE I      ##STR63##            ELEMENTARY Code    Melting ANALYSIS Num-  Empirical Molecular     point OR [α].sub.D ber Ar R R.sub.1 COA m R.sub.2 R.sub.3 n B Form f     ormula weight (°C.) % C H N                     C.H.N.    1      ##STR64##      H H      ##STR65##      0 H H 0      ##STR66##      Base C.sub.20 H.sub.25 N.sub.3 O.sub.6 403.42  165 Cal.Obt. 59.5459.18     6.256.35 10.4210.24               C.H.N. 2      ##STR67##      H H      ##STR68##      1 H H 0      ##STR69##      HCl C.sub.21 H.sub.28 ClN.sub.3 O.sub.4 421.91 >260 CalObt. 59.7859.75     6.696.94  9.969.83 C.H.N. (+1.15% H.sub.2 O)                   3      ##STR70##      H H      ##STR71##      0 CH.sub.3 H 0      ##STR72##      HCl +1.15% H.sub.2 O C.sub.21 H.sub.28 ClN.sub.3 O.sub.4 +1.15% H.sub.2     O 426.82  252 Cal.Obt. 59.0959.11 6.746.68  9.859.75 C.H.N. (+2.5%     H.sub.2      O)                4     ##STR73##      H H      ##STR74##      0 CH.sub.3 H 0      ##STR75##      Base +2.5% H.sub.2 O C.sub.21 H.sub.27 N.sub.3 O.sub.4 +2.5% H.sub.2 O     395.33 vitrousproduct  Cal. 63.797.25 10.63Obt.63.527.55 10.50 [α].     sub.D.sup.20 = +29.8°(C = 1% CHCl.sub.3) C.H.N. (+3.13% H.sub.2     O)                5      ##STR76##      H H      ##STR77##      0 CH.sub.3 H 0      ##STR78##      Base +3.13% H.sub.2 O C.sub.21 H.sub.27 N.sub.3 O.sub.4 +3.13% H.sub.2     O 397.90 vitrousproduct Cal.Obt.63.387.1910.56 63.41 7.31 10.17 [α]     .sub.D.sup.20 = -29.7°(C = 1% CHCl.sub.3)                C.H.N.      6      ##STR79##      H H      ##STR80##      0 H H 0      ##STR81##      Base C.sub.20 H.sub.23 N.sub.3 O.sub.5 385.41  163 Cal.Obt. 62.3262.03     6.026.02 10.9010.82 C.H.N. (+4.2% H.sub.2 O)                   7      ##STR82##      H H      ##STR83##      0 H H 0      ##STR84##      HCl +4.2% H.sub.2 O C.sub.23 H.sub.34 ClN.sub.3 O.sub.5 +4.2% H.sub.2 O     488.55  200 Cal.Obt. 56.5456.58 7.417.20  8.608.57               C.H.N.     8      ##STR85##      H H      ##STR86##      0 CH.sub.3 H 0      ##STR87##      Base C.sub.20 H.sub.26 ClN.sub.3 O.sub.2 375.89      170 Cal.Obt. 63.9063.85 6.977.09 11.1810.91               C.H.N. 9      ##STR88##      H H      ##STR89##      0 CH.sub.3 H 0      ##STR90##      Base C.sub.20 H.sub.26 ClN.sub.3 O.sub.2 375.89      100 Cal.Obt. 63.9063.90 6.977.32 11.1810.87               C.H.N. 10      ##STR91##      H H      ##STR92##      0 CH.sub.3 H 0      ##STR93##      Base C.sub.20 H.sub.26 FN.sub.3 O.sub.2 359.43  143 Cal.Obt. 66.8366.90 7     .297.60 11.6911.46 C.H.N. (+4.5% H.sub.2 O)                   11      ##STR94##      H H      ##STR95##      0 H H 0      ##STR96##      HCl +4.5% H.sub.2 O C.sub.20 H.sub.28 ClN.sub.3 O.sub.6 +4.5% H.sub.2 O     462.53  110 Cal.Obt. 51.9451.91 6.616.74  9.098.94 C.H.N. (+1.9% H.sub.2     O)                   12      ##STR97##      H H      ##STR98##      0 H H 0      ##STR99##      HCl +1.9% H.sub.2 O C.sub.20 H.sub.28 ClN.sub.3 O.sub.6 +1.9% H.sub.2 O     450.51 200 110 Cal.Obt. 53.3253.45 6.486.23  9.339.61 C.H.N. (+4%     H.sub.2      O)                   13     ##STR100##      H H      ##STR101##      0 H H 0      ##STR102##      HCl +4% H.sub.2 O C.sub.19 H.sub.26 ClN.sub.3 O.sub.6 +4% H.sub.2 O     445.71 >210 Cal.Obt. 51.2051.49 6.336.15  9.439.30 C.H.N. (+5.23%     H.sub.2      O)                   14     ##STR103##      H H      ##STR104##      1 H H 1 OH HCl +5.23% H.sub.2 O C.sub.18 H.sub.23 ClN.sub.2 O.sub.5     +5.23% H.sub.2 O 403.96  140 Cal.Obt. 53.5253.63 6.336.08  6.947.00     C.H.N. (+4.8% H.sub.2      O)                   15     ##STR105##      H H      ##STR106##      1 H H 2 OH HCl +4.8% H.sub.2 O C.sub.19 H.sub.25 ClN.sub.2 O.sub.5     +4.8% H.sub.2 O 416.70  214 Cal.Obt. 54.7655.00 6.586.74  6.726.77      C.H.N. (+0.6% H.sub.2      O)                   16     ##STR107##      H H      ##STR108##      1 H H 0 OH HCl +0.6% H.sub.2 O C.sub.17 H.sub.21 ClN.sub.2 O.sub.5     +0.6% H.sub.2 O 370.89 >260 Cal.Obt. 55.0555.01 5.775.57  7.557.76             C.H.N. 17      ##STR109##      H H      ##STR110##      1 H H 2      ##STR111##      Maleate C.sub.27 H.sub.35 N.sub. 3 O.sub.8 529.57  179 Cal.Obt.     61.2361.35 6.666.88  7.947.84 C.H.N. (+2% H.sub.2 O)     18      ##STR112##      H H      ##STR113##      0 H H 0      ##STR114##      HCl +2% H.sub.2 O C.sub.21 H.sub.27 ClN.sub.2 O.sub.4 +2% H.sub.2 O     415.20  205 Cal.Obt. 60.7460.50 6.787.16  6.756.60               C.H.N.     19      ##STR115##      H H      ##STR116##      0 CH.sub.3 H 0      ##STR117##      HCl C.sub.21 H.sub.30 ClN.sub.3 O.sub.3 407.93 >200 Cal.Obt. 61.8361.71 7     .417.64 10.3010.35               C.H.N. 20      ##STR118##      H H      ##STR119##      1 H H 1      ##STR120##      Maleate C.sub.26 H.sub.33 N.sub.3 O.sub.8 515.55      158 Cal.Obt. 60.5760.57 6.456.65  8.158.07               C.H.N. 21      ##STR121##      H H      ##STR122##      0 CH.sub.3 H 0      ##STR123##      HCl C.sub.20 H.sub.28 ClN.sub.3 O.sub.3 395.90  120(decompo-sition)     O     Cal.bt. 60.9860.72 7.177.50 10.6710.35               C.H.N. 22      ##STR124##      H H      ##STR125##      0 H H 0      ##STR126##      HCl C.sub.23 H.sub.34 ClN.sub.3 O.sub.5 467.98 ≃260     Cal.Obt. 59.0358.70 7.327.68  8.988.67 C.H.N. (+1.25% H.sub.2 O)               23      ##STR127##      H H      ##STR128##      0 H H 0      ##STR129##      HCl +1.25% H.sub.2 O C.sub.21 H.sub.28 ClN.sub.3 O.sub.4 +1.25% H.sub.2     O 427.26 ≃260 Cal.Obt. 59.0358.61 6.756.91  9.849.60             C.H.N. 24      ##STR130##      H H      ##STR131##      0 H H 0      ##STR132##      HCl C.sub.21 H.sub.28 ClN.sub.3 O.sub.4 421.91 >260 CalObt. 59.7859.53     6.696.72      9.969.75               C.H.N. 25     ##STR133##      H H      ##STR134##      0 CH.sub.3 H 0      ##STR135##      HCl C.sub.20 H.sub.28 ClN.sub.3 O.sub.3 393.90  100(decompo-sition)     O     Cal.bt. 60.9860.92 7.177.30 10.6710.40 C.H.N. (+3.5% H.sub.2 O)              26      ##STR136##      H H      ##STR137##      0 H H 0      ##STR138##      HCl +3.5% H.sub.2 O C.sub.23 H.sub.33 ClN.sub.2 O.sub.5 +3.5% H.sub.2 O     469.40  148 Cal.Obt. 58.0558.82 7.477.39  5.976.12 C.H.N. (+1% H.sub.2     O)                   27      ##STR139##      H H      ##STR140##      0 H H 0      ##STR141##      Oxalate +1% H.sub.2 O C.sub.24 H.sub.34 N.sub.2 O.sub.9 +1% H.sub.2 O     499.52  105 Cal.Obt. 57.7157.31 6.976.82  5.615.60 C.H.N. (+0.54%     H.sub.2      O)                   28     ##STR142##      H H      ##STR143##      0 CH.sub.3 H 0 NHCH.sub.2 COOH hemifuma-rate +0.54% H.sub.2 O C.sub.12     H.sub.25 N.sub.3 O.sub.8 +0.54% H.sub.2 O 449.86      110 Cal.Obt. 56.0755.84 5.665.86  9.349.18 C.H.N. (+2.1% H.sub.2 O)                   29      ##STR144##      H H      ##STR145##      0 CH.sub.3 H 0 NHCH.sub.2 CONH.sub.2 HCl +2.1% H.sub.2 O C.sub.19     H.sub.25 ClN.sub.4 O.sub.5 +2.1% H.sub.2 O 433.99      150 Cal.Obt. 52.5852.85 6.036.13 12.9112.87 C.H.N. (HCl)        30      ##STR146##      H CH.sub.3      ##STR147##      0 H H 0      ##STR148##      BaseHCl C.sub.21 H.sub.27 N.sub.3 O.sub.4C.sub.21 H.sub.28 ClN.sub.3     O.sub.4 385.40421.91  102200 Cal.Obt. 59.7859.64 6.696.98  9.969.60     C.H.N. (+4.22% H.sub.2      O)                   31     ##STR149##      CH.sub.3 H      ##STR150##      0 H H 0      ##STR151##      HCl +4.22% H.sub.2 O C.sub.21 H.sub.28 ClN.sub.3 O.sub.4 +4.22% H.sub.2     O 440.50  176 Cal.Obt. 57.2657.38 6.886.81  9.549.33 C.H.N. (+2.7%     H.sub.2      O)                   32     ##STR152##      H H      ##STR153##      0 CH.sub.3 H 0 OH(±) Base +2.7% H.sub.2 O C.sub.16 H.sub.19      ClN.sub.2 O.sub.3 +2.7% H.sub.2 O 331.74  120(decompo-sition) Cal.Obt.     57.9257.63 6.076.17      8.447.96               C.H.N. 33     ##STR154##      H H      ##STR155##      0 Et H 0      ##STR156##      Base C.sub.22 H.sub.29 N.sub.3 O.sub.4 399.48   95 CalObt. 66.1466.11     7.327.33 10.5210.44 C.H.N. (+5.5% H.sub.2 O)                   34      ##STR157##      H H      ##STR158##      1 H H 3 OH HCl +5.5% H.sub.2 O C.sub.20 H.sub.27 ClN.sub. 2 O.sub.5     +5.5% H.sub.2 O 434.80  120 Cal.Obt. 55.2455.31 6.876.91  6.446.65             C.H.N. 35      ##STR159##      H H      ##STR160##      1 H H 3      ##STR161##      HCl C.sub.24 H.sub.34 N.sub.3 O.sub.4 463.99  194 CalObt. 62.1262.39     7.397.28      9.068.98               C.H.N. 36     ##STR162##      H H      ##STR163##      0 H H 0 NHCH.sub.2 COOH Base C.sub.18 H.sub.21 N.sub.3 O.sub.6 375.37     220 CalObt. 57.5957.40 5.645.81 11.2010.92               C.H.N. 37      ##STR164##      H H      ##STR165##      0 CH.sub.3 H 0 OH(±) HCl C.sub.16 H.sub.20 FN.sub.2 O.sub.3 342.79     100(decompo-sition) Cal.Obt. 56.0655.87 5.885.68  8.178.19 C.H.N. (+0.9%     H.sub.2      O)                   38     ##STR166##      H H      ##STR167##      0 H H 0      ##STR168##      di HCl +0.9% H.sub.2 O C.sub.20 H.sub.30 Cl.sub.2 N.sub.4 O.sub.4 +0.9%     H.sub.2 O 465.43  222(decompo-sition) Cal.Obt. 51.6151.56 6.596.53     12.0311.90 C.H.N. (+2.5% H.sub.2      O)                   39     ##STR169##      H H      ##STR170##      0 H H 0      ##STR171##      HCl +2.5% H.sub.2 O C.sub.19 H.sub.24 ClN.sub.3 O.sub.6 +2.5% H.sub.2 O     436.78  120 Cal.Obt. 52.2452.33 5.826.02  9.629.62               C.H.N.     40      ##STR172##      H H      ##STR173##      0 H H 0      ##STR174##      HCl C.sub.19 H.sub.25 ClN.sub.4 O.sub.5 424.88  180 CalObt. 53.7153.46     5.936.09 13.1912.88               C.H.N. 41      ##STR175##      H H      ##STR176##      0 CH.sub.3 H 0 OH(±) HBr C.sub.16 H.sub.20 BrClN.sub.2 O.sub.3     403.70  220(decompo-sition) Cal.Obt. 47.6047.70 4.995.02  6.947.05     C.H.N. (+5.4% H.sub.2      O)                   42     ##STR177##      H H      ##STR178##      0 CH.sub.3 H 0 OH(±) Base +5.4% H.sub.2 O C.sub.16 H.sub.20 N.sub.2     O.sub.4 +5.4% H.sub.2 O 321.71  225(decompo-sition) Cal.Obt. 59.7359.52     6.866.70  8.718.61 C.H.N. (+2.6% H.sub.2 O)                   43      ##STR179##      H H      ##STR180##      0 CH.sub.3 H 0 OH(±) Base + 2.6% H.sub.2 O C.sub.16 H.sub.20 N.sub.2     O.sub.4 +2.6% H.sub.2 O 312.33 >250 Cal.Obt. 61.5161.61 6.746.79     8.978.89 C.H.N. (1.3 oxalate + 1.5% H.sub.2 O)                   44      ##STR181##      H H      ##STR182##      0 H H 0      ##STR183##      1.3 oxa-late +1.5% H.sub.2 O C.sub.24 H.sub.35 N.sub.3 O.sub.5 +1.3     oxalate +1.5% H.sub.2 O 571.16  105 Cal.Obt. 55.9355.66 6.877.07     7.367.34 C.H.N. (+1% H.sub.2      O)                   45     ##STR184##      H H      ##STR185##      0 H H 0      ##STR186##      Oxalate +1% H.sub.2 O C.sub.24 H.sub.31 N.sub.3 O.sub.8 +1% H.sub.2 O     494.46  142 Cal.Obt. 58.2957.90 6.436.30  8.498.07 C.H.N. (+1.6% H.sub.2     O)                   46      ##STR187##      H H      ##STR188##      0 CH.sub.3 H 0      ##STR189##      HCl +1.6% H.sub.2 O C.sub.24 H.sub.36 ClN.sub.3 O.sub.5 +1.6% H.sub.2 O     489.94  244 Cal.Obt. 55.8358.55 7.597.65  8.589.44 C.H.N. (+1.9% H.sub.2     O)                   47      ##STR190##      H H      ##STR191##      0 CH.sub.3 H 0      ##STR192##      HCl +1.9% H.sub.2 O C.sub.22 H.sub.30 ClN.sub.3 O.sub.4 + 1.9% H.sub.2     O 444.38  240 Cal.Obt. 59.4559.49 7.027.10  9.469.26 C.H.N. (+4.8%     H.sub.2      O)                   48     ##STR193##      H H      ##STR194##      0 CH.sub.3 H 0      ##STR195##      Base +4.8% H.sub.2 O C.sub.20 H.sub.25 N.sub.3 O.sub.6 +4.8% H.sub.2 O     423.59  100 Cal.Obt. 56.7156.72 6.486.59  9.9210.08               C.H.N.     49      ##STR196##      H H      ##STR197##      0 CH.sub.3 H 0      ##STR198##      Base C.sub.20 H.sub.26 N.sub.4 O.sub.5 402.44  183 CalObt. 59.6959.57     6.516.69 13.9213.89 C.H.N. (+1.05% H.sub.2 O)                   50      ##STR199##      H H      ##STR200##      0 H H 0      ##STR201##      di HCl +1.05% H.sub.2 O C.sub.22 H.sub.34 Cl.sub.2 N.sub.4 O.sub.4     +1.05% H.sub.2 O 494.63  220 Cal. Obt. 53.4153.42 7.057.10 11.3311.05                C.H.N. 51      ##STR202##      H H      ##STR203##      0 C.sub.3      H.sub.7n H 0     ##STR204##      Maleate C.sub.27 H.sub.35 N.sub.3 O.sub.8 529.57      200 CalObt. 61.2361.09 6.666.76  7.947.98 C.H.N. (+0.9% H.sub.2 O)                  52      ##STR205##      H H      ##STR206##      0 CH.sub.3 CH.sub.3 0      ##STR207##      Base +0.9% H.sub.2 O C.sub.22 H.sub.29 N.sub.3 O.sub.4 +0.9% H.sub.2 O     403.02  165 Cal.Obt. 65.5665.70 7.367.56 10.4310.21               C.H.N.     53      ##STR208##      H H      ##STR209##      0 C.sub.3      H.sub.7iso H 0     ##STR210##      Base C.sub.22 H.sub.31 N.sub.3 O.sub.4 413.50  100 CalObt. 66.8066.52     7.567.69 10.16      9.87               C.H.N. 54     ##STR211##      H H      ##STR212##      0 H H 0      ##STR213##      1.5 Maleate C.sub.26 H.sub.33 N.sub.3 O.sub.11 563.55  154 CalObt.      5     55.415.13 5.905.93      7.467.36               C.H.N. 55     ##STR214##      H H      ##STR215##      0 H H 0      ##STR216##        -- C.sub.21 H.sub.30 IN.sub.3 O.sub.5 531.38  222 CalObt. 47.4647.32     5.595.82  7.917.91 C.H.N. (+4% H.sub.2      O)                   56     ##STR217##      H H      ##STR218##      0 H H 0      ##STR219##      Base +4% H.sub.2 O C.sub.22 H.sub.27 N.sub.3 O.sub.4 +4% H.sub.2 O     413.36  Cal.Obt. 63.8263.63 7.037.18 10.1510.26               C.H.N. 57      ##STR220##      H H      ##STR221##      0 H H 0      ##STR222##      HCl C.sub.21 H.sub.28 ClN.sub.3 O.sub.4 421.91  220(decompo-sition)     CalObt. 59.7859.60 6.696.84   9.9610.15 C.H.N. (+0.75% H.sub.2 O)                58      ##STR223##      H H      ##STR224##      0 H H 0      ##STR225##      1.5oxalate +0.75% H.sub.2 O C.sub.25 H.sub.32 N.sub.3 O.sub.10 +0.75%     H.sub.2 O 538.57  220 Cal.Obt. 55.7455.90 6.066.11  7.807.82       C.H.N. 59      ##STR226##      H H      ##STR227##      0 CH.sub.3 H 0 OH HBr C.sub.17 H.sub.23 BrN.sub.2 O.sub.4 399.28     220(decompo-sition) Cal.Obt. 51.1350.96 5.815.96  7.027.07 C.H.N. (+3%     H.sub.2      O)                   60     ##STR228##      H H      ##STR229##      0 H H 0      ##STR230##      +3% H.sub.2 O C.sub.20 H.sub.25 N.sub.3 O.sub.5 +3% H.sub.2 O 399.41     150(decompo-sition) CalObt. 60.1459.99 6.636.68 10.5210.60 C.H.N. (+6.5%     H.sub.2      O)                    61     ##STR231##      H H      ##STR232##      0 H H 0      ##STR233##      HCl +6.5% H.sub.2 O C.sub.21 H.sub.27 ClN.sub.2 O.sub.5 +6.5% H.sub.2 O     452.30  175then250 Cal.Obt. 55.7655.91 6.756.69  6.196.09     C.H.N. 62      ##STR234##      H H      ##STR235##      0 H H 0      ##STR236##        --  C.sub.22 H.sub.29 N.sub.2 O.sub.5 I 528.37      212 Cal.Obt. 50.0149.84 5.535.51  5.305.37 C.H.N. (+1% H.sub.2 O)                 63      ##STR237##      H H      ##STR238##      0 H H 0      ##STR239##      HCl +1% H.sub.2 O C.sub.23 H.sub.29 N.sub.3 O.sub.4 +1% H.sub.2 O     452.48 >260 Cal.Obt. 61.0560.24 6.796.80  9.299.11               C.H.N.     64      ##STR240##      H H      ##STR241##      0 H H 0      ##STR242##      Base C.sub.23 H.sub.33 N.sub.3 O.sub.5 431.52  100(decompo-sition)     Cal.Obt. 64.0163.69 7.717.80  9.749.69 C.H.N. (+1.8% H.sub.2 O)              65      ##STR243##      H H      ##STR244##      0 H H 0      ##STR245##      Base +1.8% H.sub.2 O C.sub.23 H.sub.33 N.sub.3 O.sub. 5 +1.8% H.sub.2 O     439.43   50(decompo-sition) Cal.Obt. 62.8663.00 7.777.87  9.569.61     C.H.N. (+3% H.sub.2      O)                   66     ##STR246##      H H      ##STR247##      0 H H 0      ##STR248##      HCl +3% H.sub.2 O C.sub.21 H.sub.28 ClN.sub.3 O.sub.4 +3% H.sub.2 O     434.96   50(decompo-sition) CalObt. 58.1757.65 6.837.38  9.669.93 C.H.N. (     +3.75% H.sub.2      O)                    67     ##STR249##      H H      ##STR250##      0 CH.sub.3 H 0 OH(±) Base +3.75% H.sub.2 O C.sub.19 H.sub.26 N.sub.2     O.sub.6 +3.75% H.sub.2 O 393.43  202 Cal.Obt. 58.0458.12 7.096.58     7.127.03 C.H.N. (+1.63% H.sub.2      O)                   68     ##STR251##      H H      ##STR252##      0 CH.sub.3 H 0      ##STR253##      Base +1.63% H.sub.2 O C.sub.24 H.sub.35 N.sub.3 O.sub.5 +1.63% H.sub.2     O 452.93   50(decompo-sition) Cal.Obt. 63.6363.83 7.978.11  9.289.35     C.H.N. (+2.6% H.sub.2      O)                   69     ##STR254##      H H      ##STR255##      0 H H 0      ##STR256##      Base +2.6% H.sub.2 O C.sub.22 H.sub.29 N.sub.3 O.sub. 4 +2.6% H.sub.2 O     410.10      50(decompo-sition) Cal.Obt. 64.4364.38 7.427.51 10.2510.15

The compounds of the invention were tested on laboratory animals andshowed pharmacological activities and particularly stimulating,protecting and/or correcting activities of the cerebral functions.

These activities were demonstrated more especially by the test formnesic retention of exploratory activity in accordance with thefollowing method.

In an ACTIMETRE APELAB [BOISSIER and SIMON, Arch. Inter. Pharmacodyn.158, 212, (1965)] apparatus the exploratory activity of maleSWISS-WEBSTER mice was measured, then the animals received anintraperitoneal (or oral) injection of the compounds of the invention orof physiological serum. After a week, the exploratory activity c of thetreated animals was again measured and the effect on mnesic retentionwas measured by habituation, i.e. a statistically significant reduction(t of STUDENT by paired groups) of the exploratory activity. Toillustrate the invention, we give in table II below the results obtainedwith some compounds of the invention. The approximate acute toxicity wasmeasured by the method described by MILLER and TAINTER in Proc. Soc.Exp. Biol. Med. 57, 261 (1944). The results obtained with some compoundsof the invention are also shown by way of examples in this table II.

                  TABLE II                                                        ______________________________________                                                                    Acute                                             Code Numbers                                                                            Mnesic retention test                                                                           toxicity (mice)                                   of the    Dose      % reduction of      Mor-                                  Compounds (mice)    the exploratory                                                                           Dose    tality                                Tested    mg/kg/i.p.                                                                              activity    mg/kg/i.p.                                                                            %                                     ______________________________________                                         1        10        26.3        --      --                                     2        1         21.8        400     0%                                     6        0.01      22.7        400     0%                                     9        0.1       30.5        "       "                                     17        0.01      23.9        "       "                                     18        0.01      21.6        "       "                                     22        0.01      21.3        "       "                                     23        0.01      33.5        "       "                                     31        0.01      26.5        "       "                                     34        0.001     24.9        "       "                                     47        0.1       26.9        "       "                                     ______________________________________                                    

As these results show, the compounds of the invention have a markedpharmacological activity and a low toxicity. The pharmaceuticallyacceptable compounds of the invention find then their application intherapeutics as useful drugs more particularly for stimulatingintellectual efficiency in normal subjects, for preserving the cerebralfunction in aged subjects and for treating troubles of alertness and ormemorization, following different pathologies, particularly cranialtraumatisms, cerebral stocks and acute or sub-acute cerebrovascularaccidents.

The present invention further extends to the pharmaceutical compositionscontaining, as active ingredient, one at least of the above-defineddrugs these compositions being formulated particularly with a view tooral or parenteral administration. Thus, they may for example beadministered orally in the form of pills, capsules, tablets or of adrinkable aqueous solution, in amounts up to 2.5 g of activeingredient/day, taken in several doses (up to six doses) or parenterallyin the form of injectable ampoules containing up to 1 g of activeingredient (1 or 3 injections per day).

In the case of oral administration in the form of pills, capsules ortablets, these latter may advantageously contain a vehicle (such ascellulosic derivatives, vinyl polymers or gums) for modulating releaseof the active ingredient. The drinkable aqueous solutions will beaqueous solutions or suspensions (vehicle=water) or partially aqueoussolutions or suspensions (vehicle=water+alcohol, water+glycerine orwater+propylene glycol). Finally, in the case of parenteral injection,the active ingredient may be injected in the form of injectablesuspensions or solutions of lyophilisates containing this activeingredient.

We claim:
 1. Compounds of formula: ##STR257## wherein: Ar represents aphenyl nucleus; a phenyl nucleus substituted by one halogen atom, by oneor three alkoxy groups with 1 to 4 carbon atoms or by one or two hydroxygroups; a 1,3-benzodioxol ##STR258##
 2. 2-dimethyl-1,3-benzodioxol##STR259##
 1. 4-benzodioxanyl ##STR260## group; or a group of structure##STR261## in which p is 1 or 2; CO--A-- represents one of the followinggroups: ##STR262## where r is 0 or 1; s is 0, 2 or 3; and R₄ is hydrogenor C₁ -C₄ alkyl;B represents a group chosen from the following:pyrrolidino; piperidino; morpholino; hexamethyleneimino; ##STR263##where t is 1, 2, 3 or 4, R₄ is hydrogen or C₁ -C₄ alkyl R₅ is C₁ -C₄alkyl; when B is a heterocycle group, it is bonded to the adjacent COgroup through the hetero cycle ring nitrogen atom; R₂ and R₃ eachrepresents hydrogen or C₁ -C₄ alkyl, not however, repesentingsimultaneously an alkyl group having more than one carbon atom; and n is0, 1, 2 or 3; including the enantiomers and diastereoisomers forms andthe trans (E) and cis (Z) forms; as well as the addition salts withorganic or mineral acids or bases, the hydrates and the N-oxides ofcompounds (I); with the proviso that A cannot represent ##STR264## or##STR265## when B represents pyrrolidino, piperidino, morpholino orhexamethyleneimino.
 2. The compounds as claimed in claim 1, wherein thechain --CH═CH--CO-- is of trans (E) configuration.
 3. The compounds asclaimed in claim 2, wherein Ar is ##STR266##
 4. The compound as claimedin claim 3, of formula: ##STR267## or an addition salt thereof with acidor a base.
 5. The compound as claimed in claim 3, of formula: ##STR268##or an addition salt thereof with acid or a base.
 6. A pharmaceuticalcomposition having a memory enhancing activity, comprising atherapeutically effective amount of a compound as claimed in claim 1,with a pharmaceutically acceptable carrier.
 7. A method for enhancingthe memory which comprises internally administering to a patient atherapeutically effective amount of a compound of formula: ##STR269##wherein: Ar represents a phenyl nucleus; a phenyl nucleus substituted byone halogen atom, by one or three alkoxy groups with 1 to 4 carbon atomsor by one or two hydroxy groups; a 1,3-benzodioxol ##STR270## 2.2-dimethyl-1,3-benzodioxol ##STR271## or 1,4-benzodioxanyl ##STR272##group; or a group of structure ##STR273## in which p is 1 or 2; CO--A--represents one of the following groups: ##STR274## where r is 0 or 1; sis 0, 2 or 3; and R₄ is hydrogen or C₁ -C₄ alkyl;B represents a groupchosen from the following: pyrrolidino; piperidino; morpholino;hexamethyleneimino; ##STR275## where t is 1, 2, 3 or 4, R₄ is hydrogenor C₁ -C₄ alkyl; R₂ and R₃ each represents hydrogen or C₁ -C₄ alkyl R₅is C₁ -C₄ alkyl, not however, representing simultaneously an alkyl grouphaving more than one carbon atom; and n is 0, 1, 2 or 3; including theenantiomers and diastereoisomers forms and the trans (E) and cis (Z)forms; as well as the addition salts with organic or mineral acids orbases, the hydrates and the N-oxides of compounds (I); B however notbeing able to represent:the pyrrolidino, piperidino, morpholino orhexamethyleneimino when R₂ =R₃ =H, n=O and A= ##STR276## and thepyrrolidino, piperidino, morpholino or hexamethyleneimino when Ar is 2,3, 4-trimethoxyphenyl or 3, 4, 5-trimethoxyphenyl, the set (R₂, R₃,n)=(CH₃, H, O), (H, H, 1), (H, H, 2) or (H, H, 3) and A= ##STR277## 8.The method as claimed in claim 7, wherein the chain --CH═CH--CO-- informula (I') is of trans (E) configuration.
 9. The method as claimed inclaim 8, wherein in formula (I') Ar is ##STR278##
 10. The method asclaimed in claim 9, wherein said compound is a compound of formula:##STR279## or an addition salt thereof with an acid or a base.
 11. Themethod as claimed in claim 9, wherein said compound is a compound offormula: ##STR280## or an addition salt thereof with acid or a base. 12.The method as claimed in claim 9, wherein said compound is a compound offormula: ##STR281## or an addition salt thereof with acid or a base. 13.The method as claimed in claim 9, wherein said compound is a compound offormula: ##STR282## or an addition salt thereof with acid or a base. 14.The method as claimed in claim 9, wherein said compound is a compound offormula: ##STR283## or an addition salt thereof with acid or a base. 15.The method as claimed in claim 9, wherein said compound is a compound offormula: ##STR284## or an addition salt thereof with acid or a base. 16.The method as claimed in claim 9, wherein said compound is a compound offormula: ##STR285## or an addition salt thereof with acid or a base.